The endoplasmic reticulum plays a key role in the quality control of protein translation and posttranslational modification. Many systems within the ER are present for the detection of misfolded proteins. The selection for complexation and elimination by proteolytic degradation following retrotranslocation from the ER to the cytosol is the central tenet of this process (ERAD—Endoplasmic Reticulum associated degradation). This, in turn, regulates the unfolded protein response and other ER stress related signaling pathways.
In many, perhaps all, genetic diseases, mutations are present which do not affect the primary function of the given protein but cause some small changes in the folding of the protein within the ER, such that it is recognized as a misfolded protein to initiate this quality control mechanism, such that the protein is degraded and is not permitted to mature through anterograde transport through the Golgi/TGN/secretory vesicles to the cell surface or secretion.
Many ingenious procedures have been described which attempt to rescue such functional but nevertheless misfolded and degraded mutant proteins, to allow ERAD escape, maturation and trafficking to the correct location for functional reversal of the pathogenic phenotype. These include the use of chemical chaperones, chaperone inhibitors, enzyme substrates or inhibitors. Diseases in which such approaches are heavily studied include arthritis, cystic fibrosis, lysosomal storage diseases, aspects of dislipidemia, hypertension, cholesterol biosynthesis and α1-antitripsin disease.